Lactam precursor thienamycin

The Nicholas reaction was used to synthesize the p-lactam precursor of thienamycin in the laboratory of P.A. Jacobi and thereby accomplish its formal total synthesis. The necessary p-amino acid was prepared by the condensation of a boron enolate (derived from an acylated oxazolidinone) with the cobalt complex of an enantiopure propargylic ether. The resulting adduct was oxidized with ceric ammonium nitrate (CAN) to remove the cobalt protecting group from the triple bond, and the product was obtained with a 17 1 anti.syn selectivity and in good yield. 

Other approaches to (36) make use of (37, R = CH3) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoenzymatic synthesis for both thienamycin (2) and ip-methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH3) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), (ill. (), has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxazolidine (41) which again can be converted to a suitable P-lactam precursor (65). 

Formal syntheses of thienamycin (2) from precursors such as carbohydrates (43—45), amino acids (46,47), isoxa2ohdines (48), and tricarbonyliron lactam complexes (49) have also been reported. Many other methods for carbapenem synthesis have been widely reviewed (10,50—52). 

This aldol reaction was employed for an asymmetric synthesis of the azetidinone 9 from the adduct (5) of acetaldehyde and l.5 Azetidinone 9 is a versatile precursor to the antibiotic thienamycin 10. The configurationally stable aldehyde 6, obtained by ozonolysis of the silyl ether of 5, undergoes addition with allylzinc chloride to afford 7, which on transamination is converted to the N-methoxy amide 8. This product is converted in several steps to the desired 9 in 34% overall yield. An interesting feature of this synthesis is the early incorporation of the hydroxyethyl side chain at C6, a step that is difficult to effect after formation of the (3-lactam ring. 

Vinyloxiranes are used for facile 7i-allyl complex formation [14], The -allylic ferralactone complex 41 was prepared by oxidative addition of Fe2(CO)9 to the functionalized vinyloxirane 40 and CO insertion. Treatment of the ferralactone complex 41 with optically active a-methylbenzylamine (42) in the presence of ZnCl2 gave the 7r-allylic ferralactam complex 45 via 44. In this case, as shown by 43, the amine attacks the terminal carbon of the allylic system and then the lactone carbonyl. Then, elimination of OH group generates the 7r-allylic ferralactam complex 45. Finally the /1-lactam 46 was obtained in 64% yield by oxidative decomplexation with Ce(TV) salt. The <5-lactam 47 was a minor product (24%). The precursor of the thienamycin 48 was prepared from 46 [15,16]. This mechanistic explanation is supported by the formation of both 7r-allyllactone and lactam complexes (49 and 51) from the allylic amino alcohol 50 [17]. 

In the 3-lactam area, Grieco et al. have applied their development of substituted bicyclo[2.2.1]hep-tanes to a synthesis of the thienamycin precursor (188a), embedded in which are three contiguous asymmetric centers corresponding to C-5, C-6 and C-8 in the natural product (190). Readily obtained bromo aldehyde (187), upon treatment with the MeLi-derived higher order cuprate Me2Cu(CN)Li2 in... 

Jacobi and co-workers have applied the above Schreiber/Evans chiral boron enolate methodology to afford stereoselective routes to precursors of biologically important tetrapyr-roles [187], pyrromethanenones (114) (Scheme 4-59) [188], phycocyanin and phytochrome precursors, and P-amino acids [189], versatile intermediates for P-lactams of the carbapenem class. Generally, reaction of achiral or matched enolates with racemic cobalt complexes gave excellent selectivity. With a careful choice of mis-matched chiral enolate, moderate to good anti selectivity could also be achieved, leading to a formal total synthesis of thienamycin [190]. 

Merck s group [41] recently applied such an approach to the synthesis of the optically active thienamycin precursor 74 (Scheme 11). Namely, the 3(S)-triisopropylsilyloxybutyric acid chloride 67, readily available from methyl 3-hydroxybutyrate, was subjected to treatment with ethyldiisopropylamine and the resulting in situ generated ketene 68 was reacted with the imine 62 to afford a 7 1 mixture of the corresponding cis-P-lactams in 90% yield. The major isomer 69, upon treatment with tetrabutylammonium fluoride led to desilylation together with epimerization at C4 to form the p-lactam 70 in 78% yield. Inversion of the configuration at the hydroxyethyl side chain according to the Mitsunobu procedure [42] furnished the desired (R)-hydroxyethyl P-lactam 71... 

The utility of diketene 98 in P-lactam chemistry has also been shown by Simig and coworkers [64] to synthesize 3-acetyl P-lactams of type 116 suitable for further elaborations to ( ) thienamycin (Scheme 17). In such an approach, diketene was reacted with diethyl substituted aminomalonates 113, followed by ring closure of the resulting products 114 by treatment with sodium ethoxide in the presence of iodine. Ketalization of 115 and subsequent deethoxycarbon-ylation of 116 provided a mixture of cis and trans isomers of 117 which could be separated by column chromatography. Completion of the synthesis to the ( ) thienamycin precursor 8 could be achieved by established methods. A variant of the diketene method as source of acetylketene has been developed by Sato and Kaneko starting from a-aminoalkyl l,3-dioxin-4-ones [65]. 

Since the first report by Bergbreiter and Newcomb in 1980 [72] on the utilization of lithium enolates of esters in place of Reformatsky reagents for the construction of the azetidinone ring (Fig. 4), several research groups have applied such approach to the synthesis of carbapenem compounds. Most notably, the recent review by Georg [5g] on the synthesis of thienamycin and related P-lactams delineated the most recent advances in the P-lactam field and focuses great attention on the utilization of optically active esters of 3-hydroxy-butyric acid for an effective control of the relative and absolute stereochemistry at the carbon atoms T and 3 of the 3-(l -hydroxyethyl)azetidin-2-one 132. Inversion of the configuration at the hydroxyethyl side chain by Mitsunobu s reaction [42] and further elaboration of the peripheral functionalities leads to the formation of a variety of carbapenem precursors. 

Chiral iV-acetyloxazolidinones and 3-haloacetyl-2-oxazolidinones have also been employed by Evans and coworkers [93] to synthesize a thienamycin intermediate and monobactam precursors. Thiazolidinethiones have also been used as chiral auxiliaries in the aldol addition to produce optically active monocyclic P-lactams [94]. Miller et al. [95] (Scheme 35), employed such a strategy by using cysteine- and serine-derived thiazolidinethiones 221 and oxazolidinethiones 222 to provide direct access to hydroxamate precursors 224 of bicyclic P-lactams, like 225. 

An interesting strategy to the synthesis of thienamycin precursors via aldol addition-hydroxamate approach was developed by Fleming and Kilburn [99]. In this strategy (Scheme 40), the P-silylenolate 249 reacted with the aldehyde 250 to give the aldol product 251 in high diastereoselective fashion. Formation of the hydroxamate 252, followed by cyclization and removal of the benzyloxy group furnished the P-lactam 253. 

More recently, Bonnini and Fabio [110] reported a synthesis of (+) PS-5 starting from 2,3-epoxybutane 285 (Scheme 44), easily available by epoxidation of the monoprotected alcohol 284 according to the Sharpless method [112]. Compound 285 was oxidized to 286 and then transformed into the epoxyamide 287, which is formally related to the epoxyamide 263 prepared from L-threonine, and then cyclized to the P-lactam 288. Transformation of 288 into the (-h) PS-5 precursor 290 was accomplished in few steps according to Scheme 44. These authors also reported the synthesis of the thienamycin precursor 5 through the... 

The oxidative decomplexation chemistry has been employed for the synthesis of both p-lactones and P-lactams, such as the thienamycin precursor 4.242 (Scheme 4.84). ... 

Another report describes the conversion of methyl 3-azido-4,6-0-benzylidene-2,3-dideoxy-o(-D-glucopyranoside to the -lactam (15) (glucose numbering), another precursor for thienamycin. In this... 

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